Mechanism of cerebral edema in children with diabetic ketoacidosis

Glaser, Nicole; Wootton‐Gorges, Sandra L.; Marcin, James P.; Buonocore, Michael H.; DiCarlo, Joseph; Neely, E. Kirk; Barnes, Patrick D.; Bottomly, Jenny; Kuppermann, Nathan

doi:10.1016/j.jpeds.2004.03.045

Cited by 205 publications

(210 citation statements)

References 43 publications

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“…It may be that these effects are greater if they occur during the first phase of rapid rehydration when membrane electrolyte transport may be at its most active. Furthermore, it has recently been suggested that the subclinical cerebral oedema seen in most children with DKA [21,22], may be consistent with a vasogenic (rather than cytotoxic) mechanism, possibly representing reperfusion of previously hypoperfused tissues with the administration of fluid during treatment [23]. The administration of larger volumes of fluid as a risk factor would also be compatible with this theory, and the effects of insulin on electrolyte transport may be additive.…”

Section: Discussionmentioning

confidence: 96%

The UK case–control study of cerebral oedema complicating diabetic ketoacidosis in children

et al. 2006

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Aims/hypothesis Cerebral oedema complicating diabetic ketoacidosis (DKA) remains the major cause of morbidity and mortality in children with type 1 diabetes, but its aetiology remains unknown. Our objective was to determine the impact of baseline biochemical factors and of treatment-related variables on risk of the development of cerebral oedema in children with DKA. Materials and methods This was a national UK casecontrol study. Through the British Paediatric Surveillance Unit we identified 43 cases of cerebral oedema. Through a parallel reporting system, we also identified 2,940 episodes of DKA and selected 169 control subjects on the basis of comparable age, sex, numbers of new or known cases of diabetes and date of admission. Baseline biochemical data and treatment-related variables were extracted from the clinical notes of cases and control subjects. Results Allowing for differences in age, sex and new or known diabetes, cases were more acidotic at diagnosis of DKA (odds ratio [OR] for events in the least acidotic compared with the most acidotic tertile=0.02 [95% CI: 0.002-0.15], p<0.001). In addition, cases had higher potassium and urea levels at baseline. Calculated osmolality and baseline glucose were not significantly different. After allowing for severity of acidosis, insulin administration in the first hour .5], p=0.02) and volume of fluid administered over the first 4 h .97], p=0.01) were associated with risk. Low baseline plasma sodium and an elevated p a CO 2 also contributed to risk in the final regression model. Bicarbonate administration was not associated with increased risk of an event when corrected for acidosis. Conclusions/interpretation In this case-control study of DKA, baseline acidosis and abnormalities of sodium, potassium and urea concentrations were important predictors of risk of cerebral oedema. Additional risk factors identified were early administration of insulin and high volumes of fluid. These observations should be taken into account when designing treatment protocols.

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Section: Discussionmentioning

confidence: 96%

The UK case–control study of cerebral oedema complicating diabetic ketoacidosis in children

et al. 2006

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“…6 Some studies suggest that cerebral hypoperfusion may occur during DKA, resulting from dehydration and cerebral vasoconstriction related to hypocapnia. 7 Hyperglycemia may also potentiate ischemic neuronal injury. The observed decrease in NAA/Cr during DKA correlates with these hypoth-eses and suggests that neuronal injury may result from DKA, even in the absence of clinically apparent cerebral edema or substantial mental status changes during DKA.…”

Section: Discussionmentioning

confidence: 99%

Progressive Decrease inN-Acetylaspartate/Creatine Ratio in a Teenager with Type 1 Diabetes and Repeated Episodes of Ketoacidosis without Clinically Apparent Cerebral Edema: Evidence for Permanent Brain Injury: Fig 1.

Wootton‐Gorges¹,

Buonocore²,

Caltagirone³

et al. 2009

AJNR Am J Neuroradiol

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SUMMARY:Recent data suggest that DKA may contribute to cognitive impairment in children with type 1 DM. We measured the NAA/Cr ratio in a teenager during and following 2 separate episodes of DKA without clinically apparent cerebral edema. The NAA/Cr ratio decreased during DKA and improved following recovery. However, the NAA/Cr value was lower after the second episode of DKA (1.76) than after the first (1.97). These findings provide support for the hypothesis that neuronal injury may result from DKA.ABBREVIATIONS: BUN ϭ blood urea nitrogen; Cr ϭ creatine; DKA ϭ diabetic ketoacidosis; DM ϭ diabetes mellitus; NAA ϭ N-acetylaspartate S everal studies suggest that type 1 DM can lead to long-term alterations in cognitive function, and some studies have documented structural abnormalities of the brain in individuals with type 1 DM.1,2 The cause of brain injury in type 1 DM is not well understood, but recent data suggest that DKA may be strongly associated with cognitive impairment in children.3 Children who experienced an episode of DKA showed significantly decreased memory capacity compared with children with type 1 DM without a history of DKA.3 These data suggest that DKA may be an important factor causing permanent cerebral injury. Case ReportA 14-year-old boy with type 1 DM experienced 2 episodes of DKA, separated by 2 months, without clinically apparent cerebral edema. At the first presentation of DKA, his initial blood glucose level was 780 mg/dL; pH, 6.99; serum bicarbonate level, 8 mmol/L; and BUN level, 20 mg/dL. At the time of the second presentation, his initial blood glucose level was 986 mg/dL; pH, 6.98; serum bicarbonate level, 8 mmol/L; and BUN, 27 mg/dL. He had normal mental status at presentation and maintained normal mental status (hourly Glasgow Coma Scale scores of 15) during both episodes, suggesting that he did not develop clinically relevant cerebral edema.This case review was approved by our institutional review board. MR spectroscopy was performed on a 3T imaging system (8-channel Excite HD, OS Version 12M5; GE Healthcare, Milwaukee, Wisconsin) at 2 time points: 9 -12 hours after initial presentation of DKA and after recovery from the episode (Ͼ72 hours after treatment, after resolution of metabolic acidosis and ketosis). A single voxel (8 cm 3 ) at the right basal ganglia was studied using a Probe-P sequence with a TR/TE of 1500/144 ms. The NAA peak was identified according to its chemical shift at 2.02 ppm, and Cr, at 3.02 ppm. The heights of the peaks, which reflect the relative corresponding metabolite concentrations, were used to calculate the ratio of NAA/Cr. The basal ganglia were chosen as the point of interrogation because this region is especially susceptible to injury caused by DKA-related cerebral edema. The NAA/Cr ratio was lower during acute DKA than after recovery in both episodes (1.87 versus 1.97 for the first episode, 1.56 versus 1.76 for the second episode, Fig 1). More important, the NAA/Cr ratio was lower after recovery from the second episode of DKA (1.76) than after reco...

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“…Since we did not find any signs of necrosis in the DKA brains is possible that C5b-9 could result in a sublethal attack and a protective effect on CPE. The potential protective effect of sublethal attacks by C5b-9, may explain the infrequent occurrence of clinical BE in DKA (Edge et al, 2001) despite the significant prevalence of subclinical BE (Hoffman et al, 1988;Durr et al, 1992;Glaser et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Neuroinflammatory response of the choroid plexus epithelium in fatal diabetic ketoacidosis

Hoffman

Casanova

Cudrici

et al. 2007

Experimental and Molecular Pathology

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A systemic inflammatory response (SIR) occurs prior to and during the treatment of severe diabetic ketoacidosis (DKA). IL-1β, TNF-α and C5b-9 are components of SIR and have been speculated to be involved in the clinical brain edema (BE) of DKA. We studied IL-1β, TNF-α, C5b-9, inducible nitric oxide (iNOS), ICAM-1, IL-10 and Hsp70 expression in the brains of two patients who died as the result of clinical BE during the treatment of DKA. IL-1β was strongly expressed in the choroid plexus epithelium (CPE) and ependyma, and to a lesser extent in the hippocampus, caudate, white matter radiation of the pons, molecular layer of the cerebellum and neurons of the cortical gray matter. TNF-α was expressed to a lesser extent than IL-1 β, and only in the CP. C5b-9, previously shown to be deposited on neurons and oligodendrocytes, was found on CPE and ependymal cells. iNOS and ICAM-1 had increased expression in the CPE and ependyma. Hsp70 and IL-10 were also expressed in the CPE of the case with the shorter duration of treatment. Our data demonstrates the presence of a multifaceted neuroinflammatory cytotoxic insult of the CPE, which may play a role in the pathophysiology of the fatal brain edema of DKA.

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Mechanism of cerebral edema in children with diabetic ketoacidosis

Cited by 205 publications

References 43 publications

The UK case–control study of cerebral oedema complicating diabetic ketoacidosis in children

The UK case–control study of cerebral oedema complicating diabetic ketoacidosis in children

Progressive Decrease inN-Acetylaspartate/Creatine Ratio in a Teenager with Type 1 Diabetes and Repeated Episodes of Ketoacidosis without Clinically Apparent Cerebral Edema: Evidence for Permanent Brain Injury: Fig 1.

Neuroinflammatory response of the choroid plexus epithelium in fatal diabetic ketoacidosis

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